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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    614—Metabotropic Glutamate Receptors: Pharmacology and Physiology

    Tuesday, November 12, 2013, 1:00 pm - 5:00 pm

    614.16: Inhibition of the group I mGluRs reduces acute brain damage and improves long-term histological outcomes after photothrombosis-induced ischemia

    Location: Halls B-H

    ">*H. LI1, N. ZHANG1, G. SUN2, S. DING1;
    1Dalton Cardiovasc. Res. Ctr., 2Dept. of Biochem., Univ. of Missouri, Columbia, MO

    Abstract Body: Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are G protein-coupled receptors and play important roles in physiology and pathology. Studies on the role of them in cerebral ischemia have provided controversial results. In this study we used a photothrombosis (PT)-induced ischemia model to investigate whether antagonists to the group I mGluRs may offer acute and long-term protective effects in adult mice. Our results demonstrated that administration with mGluR5 antagonist MPEP or mGluR1 antagonist LY367385 by intraperitoneal injection at 3 hr after PT decreased brain infarct volume evaluated one day after ischemia. Additive effects on infarct volume were observed upon co-injection with MPEP and LY367385. These antagonists also significantly alleviated neurodegeneration and apoptosis in the penumbra. In addition, when evaluated 2 weeks after PT, they reduced infarct volume and tissue loss, attenuated glial scar formation, and inhibited cell proliferation in the penumbra. Importantly, co-injection with MPEP and LY367385 reduced the expression levels of calpain, a Ca2+-activated protease known to mediate ischemia-induced neuronal death. Injection of calpeptin, a calpain inhibitor, could inhibit neuronal death and brain damage after PT but injection of calpeptin together with MPEP and LY367385 did not further improve the protective effects mediated by MPEP and LY367385. These results suggest that inhibition of group I mGluRs is sufficient to protect ischemic damage through the calpain pathway. Taken together, our results demonstrate that inhibition of group I mGluRs can mitigate PT-induced brain damage through attenuating the effects of calpain and improve long-term histological outcomes.

    Lay Language Summary: Inhibition of the group I mGluRs reduces acute brain damage and improves
    long-term histological outcomes after photothrombosis-induced ischemia
    Hailong Li1.2, Nannan Zhang1, Grace Sun3, Shinghua Ding1,2*
    1Dalton Cardiovascular Research Center, 2Dept. of Biological Engineering,
    3Dept of Biochemistry
    University of Missouri-Columbia, MO 65211
    Stroke is the second most common cause of death world widely and 1/6 of all human beings suffer at least one stroke in their lives. Furthermore, stroke is the leading cause of adult disability. Approximately one third of patients who survive 6 months are dependent on others. Ischemic stroke accounts for approximately 80% of all strokes and results from a thrombotic or embolic occlusion of a major cerebral artery or its branches. Glutamate is the major excitatory neurotransmitter in the CNS. The vast amount of glutamate release and the subsequent Ca2+ overloading after brain injury, including ischemia, is excitotoxic. Glutamate excitotoxicity is the primary cause of acute neuronal death (necrosis) and initiates apoptosis after ischemia. Although many studies have investigated the role of group I metabotropic glutamate receptors (mGluRs) in ischemia, the underlying basic mechanisms have not been well understood. Group I metabotropic glutamate receptors, including mGluR1 and mGluR5, are G-protein-coupled receptors and play important roles in physiology and pathology. Studies on the role of them in cerebral ischemia have provided controversial results. Our aim in this study was to investigate whether the inhibition of group I metabotropic glutamate receptors can reduce brain damage after ischemic stroke in adult mice, and to further investigate whether it can improve long-term stroke outcomes.
    To test this hypothesis, we used well-established photothrombosis-induced ischemia mouse model to mimic human stroke, which generated highly reproducible infarct volume. We measured the brain infarction, neurodegeneration and apoptosis in the penumbra. We also detected the tissue loss, glial scar formation and cell proliferation in order to evaluate long-term outcomes. Using the PT-induced ischemia model in adult mice, we observed the following findings in the present study: (1) A single injection of the mGluR5 antagonist, MPEP, or the mGluR1 antagonist, LY367385, could produce brain protective effects in ischemia, and their co-injection with the same dosage further reduced the infarct volume. Data from FJB and TUNEL staining confirmed the effects of MPEP and LY367385 on reduction of neuronal degeneration and apoptotic cell death. (2) A single co-injection of MPEP and LY367385 could exert a long-term neuroprotective effect by reducing infarction and tissue loss evaluated 2 weeks after PT. (3) Based on results of Western blot analysis, co-injection of MPEP and LY367385 effectively reduced PT-induced Ca2+-activated protease calpain expression in the ischemic hemisphere. Calpain inhibitor calpeptin alone reduced the infarction and neuronal death after PT but injection of calpeptin together with MPEP and LY367385 did not further improve protective effects as compared with the injection of the antagonists. These results suggest that the brain protective effect mediated by MPEP and LY367385 is at least partially through the suppression of calpain. (4) Co-injection of MPEP and LY367385 could attenuate glial scar formation and cell proliferation in the peri-infarct region at 2 weeks after ischemia.
    Taken together, the present study provides evidence that group I mGluRs play an important role in neuronal death and damage in adult mice after ischemia. The protective effects of the antagonists are associated with the suppression of ischemia-induced increase in Ca2+-activated calpain. In addition, inhibition of group I mGluRs can also improve long-term histological stroke outcomes and attenuate glial scars and cell proliferation in the penumbra. However, further studies with cell-type specific knockout mice are needed to distinguish the role of neuronal and astrocytic group I mGluRs in ischemia.